Secondary alkylsulfonamido benzoic acids



Patented Oct. 20, 1953 SECONDARY ALKYLSULFONAMIDO BENZOIC ACIDS James Maurice Sprague, Drexel Hill, Pa., assignor to Merck & 00., Inc., a corporation of New Jersey No Drawing. Application October 21, 1950, Serial No. 191,499

6 Claims. (CL 260-518) This invention relates to new compounds having the general formula oooH R-S oi-Nnare particularly effective agents for this purpose.

All of the compounds embraced by the above structural formula are prepared by the same general procedure, namely, the condensation of a secondary-alkylor cycloalkyl sulfonyl halide with an amino benzoic acid ester in the presence of an acid binding solvent, such as pyridine or diethylaniline followed by hydrolysis of the resulting sulfonamido benzoic acid ester.

The sulfonyl halide intermediates, some of which are new substances, are advantageously prepared by one of two modifications of the isothiourea procedure. According to the usual isothiourea procedure, alkyl sulfonyl chlorides are prepared by the chlorination of isothiourea salts in aqueous solutions. This method is hazardous, however, since the nitrogen trichloride byproduct of the reaction can cause severe explosions. Each of the modified procedures overcomes this hazard by avoiding the presence of nitrogen-containing compounds during the chlorination. One of the modified procedures involves the preparation of isothiouronium salts from an alkyl halide and thiourea. These salts are known to decompose in alkaline solution to give mercaptans, which, on chlorination in aqueous medium, yield sulfonyl chlorides. The introduction of this extra step gives a safe method for the preparation of the desired sulfonyl chlorides. The procedure according to this modification is graphically represented as follows:

NH 1 811mm 01, R-S- nx R-SH R-SOZC].

In most cases, the alkanesulfonyl chlorides 2 could be distilled under diminished pressure, and, since the alkyl chlorides react readily with thiourea, a good yield of the sulfonyl chloride results on chlorination.

The procedure according to this modification requires that equimolar portions of the alkyl halide and thiourea be heated in alcohol. Advantageously, 1 ml. of alcohol per gram of alkyl halide is used. The heating is continued until very little or no black precipitate results when a 5% silver nitrate solution is added to a sample of the mixture that had been made basic with excess ammonium hydroxide. The alcohol is then removed and the residue dissolved in a minimum quantity of water. A solution of sodium hydroxide, advantageously a 40% solution, is added in small portions with stirring until no more cloudiness develops. An oil separates which is removed from the aqueous phase and dissolved in acetic acid, using about to 390 mls. of acid per mole of reactant. Cracked ice, about 50 grams per mole of reactant, is added, the mixture chilled, preferably to about 0 and saturated with chlorine or bromine. Further additions of ice are made as needed to maintain the temperature at less than 15. The sulfonyl chlorides are isolated by extracting the reaction mixture with ether, washing the extract with dilute sodium bisulfite solution and water and then drying over calcium chloride. The extract is then filtered and the ether removed by heating on a steam bath under reduced pressure for about 25 minutes. Generally, the sulfonyl halides can be further purified by distillation with only slight decomposition.

The second modification involves the preparation of isothiouronium salts by reaction of the appropriate alcohol with thiourea in the presence of concentrated hydrochloric or hydrobromic acid. This reaction can be graphically illustrated as follows:

HX R-OH HiN-OS-NH:

ammonia test for thiourea is negative. The excess alcohol is then removed under reduced pressure (about mm.) until the residue crystallizes or becomes quite viscous and completely water soluble. The residue is dissolved in water, sodium hydroxide added, the mercaptan removed and chlorinated as described above. The .sulfonyl chlorides obtained can be distilled with substantially no decomposition.

The secondary-alkyl or cycloalkyl sulfonyl halide prepared by either procedure "is added to a solution of an alkyl aminobenzoate dissolved in an acid binding solvent, such :as pyridine. The reactants can be used in equ'imolecular quantities, although a preferable ratio of reactants is 1.2 to 1.5 parts of the amine to .1 part of .sulfonyl halide; the latter ratio minimizes the formation of the disulfonyl derivative. The sulfonyl halide can be added rapidly, rarely requiring cooling.

The reaction mixture is allowed to stand at room temperature for from about 3 to 15 hours. Concentrated hydrochloric acid, 36% .(a'vo'lume equal to the quantity of acid binding solvent used) is added and the mixture diluted to about three times its volume with cold water or crushed ice. The crude carbalkoxyealkanesulfonanilides thus obtained are low melting solids and generally separate at this point as oils that solidify upon standing. The crude ester is separated from the aqueous phase by filtration or decantation and then washed with cold water. The ester is heated for approximately 1 to 2 hours in about 2 equivalents (based on the amount of the starting materials) of dilute sodium hydroxide solution.

After treating the solution with decolorizing carhen, the carboxy-alkanesulfonanilide .is precipitated from the filtrate by making the solution acid to Congo red advantageously "with concentrated hydrochloric acid. The products are purified by reprecipitation from an alkaline solution and recrystallization from aqueous alcohol, benzene or toluene.

The preparation of the new compounds of this invention is more completely illustrated by, but not restricted to, the following examples:

Example I.p C'arbory '1 methyl 1 butanesulfonanilide (a) 127 gms. (0.85 mole) of Z-bromopentane and 5'? gms. (0.75 mole) of thiourea were heated O in 150 mls. of alcohol on the steam bath for .18 hours. At the end of this time no black precipitate resulted when a sample was added to ammoniacal silver nitrate. Solvent was removed on the steam bath with the aid of a water .pump. The residue did not solidify even after standing in the refrigerator for five days. The crude S-2- pentyl isothiourea hydrobromide was dissolved in 500 mls. of water and 150 mls. of sodium hydroxide solution then was added. The oil that separated was removed, washed with water and then dissolved in 200 mls. of acetic acid. Fifty gms. of cracked ice was added to the solution and the mixture was saturated with chlorine at 0 adding ice as needed to control the temperature. The crude 1-methyl -1--butanesulfonyl chloride was extracted with ether, the ether washed with dilute sodium bisulfite solution and water and then dried over calcium chloride for three hours. The yield of crude product was 100 gms. It can be distilled, -=bo'iling at -95 at 9 mm. pressure.

(12-) To gms. (0.57 mole) of ethyl p-aminobenzoate in 125 mls. of dry pyridine, gms. (0.58 mole) of the crude sulfony-l chloride above was added. A little cooling was necessary only after about 15 minutes. After standing overnight at room temperature, mls. of concentrated hydrochloric acid and 200 gms. of cracked ice were added. This precipitated an oil which could be crystallized from isopropyl ether giving p carbethoxy 1 methyl 1 butanesulfonanilide, M. P. =86-88".

(c) The crude oily ester from above was heated in200 mls. of 10% sodium hydroxide solution on the steam bath for threefourths of an hour.

solution was treated with decolorizing carbon and filtered. The product was precipitated from the filtrate by the addition of concentrated hydrochloric acid to the Congo red end point. After reprecipitation from sodium bicarbonate solution with acetic acid and recrystallization from benzene, the yield was 34.5 gms. of p-carboxyl-lmethyl-l-butanesulfonanilide, M. P. 119-121".

Example II.--p Carbory 1 ethyl 1 propanesulfonanilide (a) Molar quantities of sebromopentane (151 gms.) and thiourea (75 gms.) in 200 mls. of alcohol were heated for 18 hours on the steam bath. A negative thiourea test was obtained with ammoniacal silver nitrate. The alcohol was removed under reduced pressure. The residue did not solidify. The crude S-3-pentylisothiourea hydrobromide was dissolved in 400 mls. or" water and 150 mls. of 40% sodium hydroxide were added. The oil that precipitated was separated and dissolved in 300 mls. of acetic acid. After the addition of 50 gms. of cracked ice, the solution was saturated with chlorine at '0 to 15 with additions of cracked ice as necessary to control the temperature. The suspension then was extracted with ether, the extract washed with dilute sodium bisulfite solution and water and then dried over calcium chloride for .3 hours. The solution then was filtered and the ether removed on the steam bath. The residue was distilled under reduced pressure giving 86 gms. (50%) of 1-ethyl-1-propanesulfonyl chloride boiling at 82-83 at 6 mm.

(b) The 86 gms. (0.5 mole) of distilled sulfo'nyl chloride was added to 82 gms. (0.5 mole) of ethyl p-aminobenzoate in 125 mls. of dry pyridine. The reaction was allowed to stand at room temperature overnight, then 125 mls. of concentrated hydrochloric acid was added and about 400 gms. of cracked ice. An oil separated which became quite viscous and could be crystallized from 'isopropyl ether giving p-carbethoxy-lethyl-l-propanesulfonanilide, M. P. 32-84.

(0) The crude oily ester was heated on the steam bath in 400 mls. of 10% sodium hydroxide for 1 hour. The solution was treated with decolorizing carbon, and filtered. The product was precipitated from the filtrate by addition of an excess of concentrated hydrochloric aicd. .Recrystallization from toluene gave 36.6 gms. of p-carboxy-l-ethyl-l-propanesulfonanilide, M. P. 125-127".

Example IlI.- p Carbomy 1,3 dimcthgi .1-

butanesulfonanilide (a) 60 gms. of thiourea (0.8 mole) and 138 gms. (0.83 mole) of 4-methyl-2-bromopentane were heated together in 150 mls. of alcohol for 18 hours on the steam bath. On removal of the solvent, the product crystallized. The S-('l,3-dimethyl-butyl) -isothiourea hydrobromide crystallized from water with a M. P. of -13'7.

(b) The crude isothiourea salt was dissolved in mls. of water and 100 mls. of 40% sodium hydroxide was added. The oil which separated The sulfonyl' solution was filtered, the solvent removed and y the residue distilled in vacuo. The yield was 562 gms. of 1,B-dimethyl-l-butanesulfonyl chloride boiling at 84-85 at 6 mm. (36%) with 12 1.4592.

(c) The 56 gms. (0.3 mole) of distilled sulionyl chloride was added to 75 gms. (0.45 mole) of ethyl p-aminobenzoate in 100 mls. of dry pyridine. The

reaction was allowed to stand overnight at room 4 temperature after which 100 mls. of concentrated hydrochloric acid and about 400 gms. of cracked ice were added. This precipitated p-carbethoxy- 1,S-dimethyl-l-butanesulfonanilide as an oil which soon solidified. A sample recrystallized to constant melting point from isopropyl ether melted at l08105.

(d) The crude ester from above was heated in 200 mls. of 10% sodium hydroxide solution on the steam bath for one hour. The solution was treated with decolorizing carbon and filtered. The filtrate was made acid to Congo red with concentrated hydrochloric acid which precipitated an oil that soon solidified. Repeated recrystallization from toluene gave 28 gms. of pcarboxy 1,3 dimethyl 1 butanesulfonanilide, M. P. l56-157.5.

Example I V.p-Carboa:' -1 -meth yZ-1 pentanesalfonanilide (a) l-methyl-l-pentanesulfonyl chloride was prepared in 60% yield from crude 2-bromohexane by a procedure similar to that described in step (a) of Example I. It boiled at 87-90 at 5 mm., 11 1.4622.

(b) To 62 gms. (0.37 mole) of ethyl p-aminobenzoate in 100 mls. of dry pyridine, 88 gms. (0.47 mole) of 1-methyl-l-pentanesulfonyl chloride was added. After standing overnight, 100 mls. of concentrated hydrochloric acid and 200 gms. of ice were added. An oil precipitated which solidified in 3 hours. Repeated recrystallization from isopropyl ether gave p-carbethoxy-l-methyl-l-pentanesulfonanilide, melting at 92-94".

Hydrolysis of the above ester by heating in 500 mls. of 10% sodium hydroxide for 1 hour yielded, after reprecipitation from sodium bicarbonate solution with acetic acid, and two recrystallizations from toluene, 17.3 gms. of pcarboxy-l-methyl-l-pentanesulfonanilide, M. P. 162-164".

Example V.--p-Carb0xy-cyclohemanesuljonam'lide (a) Cyclohexanesulfonyl chloride (32.5 gms., 0.18 mole), prepared by reacting cyclohexanol with thiourea as described by Sprague & Johnson, Journal of American Chemical Society, vol. 59, page 1837 (1937), was added to 50 gms. (0.3 mole) of ethyl p-aminobenzoate in 75 mls. 01. dry pyridine. After standing overnight at room temperature, 80 mls. of concentrated hydrochoric acid and 200 gms. of cracked ice were added. p- Carbethoxyoyclohexanesulfonanilide precipitated as an oil which solidified almost immediately. A sample repeatedly recrystallized from alcohol or benzene melted at ll-153.

(b) By heating the above crude ester in 250 mls. of sodium hydroxide solution on the steam bath for one and one-half hours, it was 6. treated with decolorizing carbon and filtered. The product was precipitated by the addition of excess hydrochloric acid to the filtrate. The precipitate was dissolved in ethyl acetate and some insoluble material removed by filtration.

The product was recovered by complete evaporation of the solvent. It was then reprecipitated I from alkaline solution with acetic acid and crystallized from 30% aqueous alcohol. The yield was 16.7 gms. 0t p-carboxy-cyclohexanesulfonanilide, M. P. l74-176.

Example VI .p-Carboay-1 -methyl-1 hexanesulfonanilide (a) l-methyl-l-hexanesulfonyl chloride was prepared by a modification of the method described by Johnson and Sprague, Journal of American Chemical Society, vol. 58, page 1351 (1936) for alkyl sulfonyl halides. After heating 400 mls. of heptanol-2, 150 gms. of 48% hydrobromic acid and gms. (0.6 mole) of thiourea on the steam bath for 24 hours, a sample was removed, made basic with ammonium hydroxide and 5% silver nitrate added. A brown precipitate indicated very little thiourea present. The solvent was removed from the bulk leaving a product with glue-like consistency which did not solidify overnight. This product was dissolved in 250 mls. of water and treated with mls. 01 40% sodium hydroxide. The oil that formed was separated, dissolved in 150 mls. of acetic acid and chlorinated at 0 to 15 in the presence of some ice. The oil was isolated as usual by ether extraction. The yield was gms. of crude l-methyl-l-hexanesulionyl chloride. It distilled only with decomposition at 105 at 5 mm. pressure, n 1.4592.

(b) 65 gms. (0.32 mole) of l-methyl-l-hexanesulfonyl chloride and 79 gms. (0.48 mole) of ethyl p-aminobenzoate were condensed in 150 mls. of dry pyridine. After standing overnight the p carbethoxy 1 methyl l hexanesulfonanilide was isolated by the addition of 150 mls. of concentrated hydrochloric acid and 300 gms. of ice. A sample repeatedly recrystallized from isopropyl ether melted at 103-105".

(c) The above crude ester was hydrolyzed by heating in 400 mls. of 10%. sodium hydroxide for one and one-half hours. Acidification of the solution precipitated the product which was purified by repeated recrystallization from toluene. The yield was 36 gms. of p-carboxy-l-methyl-lhexanesulfonanilide, M. P. l7l-173.

Example VII.-p-C'arboxy-1-methylheptanesalfonanilide (a) l-methyl-1-heptanesulfonyl chloride was prepared in 66% yield by the method described in step (a) of Example I. The boiling point was 94-98" at 2 mm.,n 1.4600.

(b) The l-methyl-l-heptanesulfonyl chloride (70 gms., 0.33 mole) and ethyl p-aminobenzoate (79 gms., 0.48 mole) were condensed in 100 mls. of dry pyridine. The p-carbethoxyl-l-methyl-1- heptanesulfonanilide was isolated as an oil after the reaction had stood overnight by adding 100 mls. of concentrated hydrochloric acid and 250 gms. of cracked ice. A sample, when repeatedly recrystallized from isopropyl ether, melted at 86-88", resolidifying and remelting at 95-97 The melting point was unchanged by drying for 2 hours at 56 and 1 mm. over phosphorus pentoxide.

(c) p Carboxy-l-methyl-l-heptanesulfonanhydrolyzed to the free acid. The solution was Hide was precipitated from 400 mls. of 10% soendear hydroxide. after heating the ester from. one and. one-half. hours.) by: the addition of. ex: cess. concentrated hydrochloric: acid. Three;- re. crystallizationsz gave 27.6- gms. of pure product,. M. P. 161-1635:

Example VIIL-pCarbon-1-propyl-1 butanesuljonanilide- (a) L-propyl-l-butanesulfonyl chloride was prepared in yield by the; method describedin step (a) of Example VI using di-n-propylcarbinol. It boiled at 90-92 at 2 mm.,. 12 124618.

(b) p Carbethoxy- I-DI'OPYl-rE-bllt8fl65lllf0hanilide was prepared by condensing, 16 g. (0.08 mole) of. the above sulf'onyl. chloride with l'6'.5 g. (0.1. mole) of ethyl p-aminobenzoate' in 11118. oi pyridine. The crude ester was isolated i'nthe usual way.

(c) By hyd'rolyzing, the crude ester 111.200 mls. of 5%. sodium hydroxide solution.- andrecrystale lizatibn. from toluene, then from benzene; 2111 g. of p-carboxy-I-propyl-I-hutanesuIfonaniIide, M..P. 130-132., was obtained.

All temperatures are. in degrees. centigrade.

While. certain specific p-carboxy-(secondaryalkyl) sul'fonanilides and certain specific p-carboxy-(cycloalkyl) sul'fonanilides are described. the above examples, other. earhoxy-(second'aryalkyl) sulfonanilides and other carboxy-(cyclbalkyl) sulfonanilid'es embraced withinthe scope. of the generic formula above can he. prepared by the. process. described. wherein. the carboxyll radical can be attached. to the orthometa.- or

para-position ofthe benzene nucleusinrelation.

wise, the various. other reactants used. in the process can be replaced. by other. chemically equivalent substances. which. one. skilledin this art can readily select in order to facilitate the reaction. of the different. intermediates employed.

in making. the desiredend product.

Changes. and variations from the foregoing. illustrations can he made. within the. scope of the invention defined. in the specification and claims annexed hereto.

what'iseclaime'd is:-

1. A new carboxy sulionanilide having the general formula.

Resor-NELOeo 0H wherein R is a secondary-aliphatic hydrocarbon radicaLeonta-ming from?) to-8 carbon atoms and.

selected? from the. group: consisting; or. an openchain secondary alkylr radical and a cycloalkylradical.

2..lihenew compound, p-carboxy-l-ethyl-lpropanesulionanilide having the" structural for-- mula.

cm-one-iirr-s Og-NHOC'O'OH 3: The new compound, p-carboxy- -l-methyl-lpentanesulfonanilide" having the structural: formula.

. om-ulnm-gnsor-Nn-Ocootr eL'Ihe. new compound, p-carboxy-cyclohexanesulfonanilide having the structural formula 5: The new compound, p-carboxyd-methyl} l-heptanesul'fonanilide having the structural formula 6. The new compound, pcarboxy-1,3-dimethyl-l-butanesulfonanilide having the" structural formula References Gi'ted in the file of this patent UNITED STATES PATENTS OTHER; REFERENCES Jones; Chem; Abstract, vol; 28, p: 2689- (I934).

Crosson et al., Chem; Abstracts; vol. 42, p; 284" 

1. A NEW CARBOXY-SULFONANILIDE HAVING THE GENERAL FORMULA 